Viruses have evolved various strategies to exploit and manipulate host cell signaling pathways for their own purposes. In particular, viruses can modulate cellular apoptosis, which is largely antiviral in consequence, in order to increase their fitness and to complete their replication cycle. Even though some viruses promote apoptosis at the late stage of viral replication to facilitate viral release and spread, in some circumstances, virus-infected cells that do not undergo apoptosis are also known to play an important role in persistence as viral reservoirs. Consequently, restoring host cell apoptotic response against viral infection, and the destruction of the infected cell, constitutes an interesting antiviral strategy.
Viral infections are also known to induce multiple cellular stress responses and, as a result, viruses often modulate host stress responses, thought the upregulation of host cell stress-related genes, for their infection. Therefore, targeting of stress-response genes could lead to effective new antiviral therapies selectively aiming the infected cells.
There is a clear unmet medical need for safer, more effective drugs to combat viral infections, from HIV to the common cold. There is also a need for therapeutics effective against large spectrums of viruses, allowing their use in clinical settings where identifying pathogenic agents might be challenging. Consequently, the development of novel antiviral strategies combining reduced negative side effects with improved efficacy and which also have novel mechanisms of action are sought. In the case of HIV infection, the introduction of combination antiretroviral therapy (cART) has successfully reduced mortality and morbidity for infected patients who have access to the treatment. However, although cART is extremely efficient in controlling HIV replication it cannot eradicate the infection from the organism. HIV integrates its genetic information in the host cell genome, establishing viral reservoirs that escape immune surveillance and action of current therapies. As a consequence HIV replication readily resumes if treatment is interrupted and anti-HIV therapies have to be maintained for life. Long-term therapy can result in enhanced adverse effects that are complicated by overlapping toxicity profiles. Moreover, as they mostly target virus-coded products, antiviral drugs may encounter resistance problems due to the emergence of resistant viruses.
Accordingly, it is of the outmost priority to develop new therapeutic approaches and drugs that specifically target the infected cell rather than the viral replication and that will be suitable for effective and efficient treatment of viral infection and latent viral infection. In this way, it has been suggested that characterization of new therapeutic compounds in viral infection and latent viral infection may be highly desirable. One of the major difficulties to achieve such selective targeting is that there are not markers available allowing the identification of HIV-infected cells.
In this context, the inventors have discovered that the stress-related, anti-apoptotic protein AAC-11 is up-regulated upon HIV infection and contributes to cell survival of HIV infected cells. Inhibition of AAC-11 induce the specific cell death of infected cells or virus producing cells, including primary CD4+ T cells and macrophages, which are the main cell targets for HIV infection, and represent a novel therapeutic strategy to eradicate or control viral infections. Inhibition of AAC-11 may also induce specific cell death in sanctuaries sites as well as latently infected cells or cells producing low levels of virus.
There is no disclosure in the art of AAC-11 inhibitors effects in viral infection, the use of the AAC-11 inhibitors in the treatment of viral infection and the treatment of latent viral infection.